We are continuing our studies to attempt to develop a model of diabetic retinopathy in rats made diabetic with streptozotocin, and in addition to investigate other aspects of the pathologic anatomy and physiology of other tissues in the eyes, brains, and other organs of these animals. In addition to diabetes, other conditions are superimposed in our attempt to promote the development of retinopathy. These include systemic hypertension in a strain of rat in which this is a genetic lesion, and diets high in sucrose. The role of aldose reductase is investigated by observing the effects of the drug CP-45634, an inhibitor of this enzyme and by feeding some animals diets rich in galactose. The role of diabetes is investigated by use of insulin therapy in some animals. After one year on these regimens, animals are sacrificed, and flat mounts of the retinal vessels are prepared by trypsin digestion. The anatomical configuration and permeability of the retinal vessels and of the retinal pigment epithelium are investigated by electron microscopy using the tracers horseradish peroxidase and microperoxidase. In addition, we will examine by light and scanning and transmission electron microscopy cerebral vessels, sciatic nerves and kidneys of animals on the various regimens. Observations will be recorded by several individuals who are masked as to the identities of the experimental animals to avoid bias. In this way, we can objectively determine what abnormalities are present that are related to diabetes.